Journal
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
Volume 11, Issue 17, Pages 7267-7272Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.0c01894
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Funding
- Ministry of Science and Technology of China [2019YFA0508400, 2016YFA0500700]
- National Natural Science Foundation of China [21874123, 21703254, 21807095]
- Fundamental Research Funds for the Central Universities [WK2060190086]
- Hefei National Science Center Pilot Project Funds
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The coronavirus disease pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the global healthcare system. As low-molecular-weight drugs have high potential to completely match interactions with essential SARS-CoV-2 targets, we propose a strategy to identify such drugs using the fragment-based approach. Herein, using ligand- and protein-observed fragment screening approaches, we identified niacin and hit 1 binding to the catalytic pocket of the main protease (M-pro) of SARS-CoV-2, thereby modestly inhibiting the enzymatic activity of M-pro. We further searched for low-molecular-weight drugs containing niacin or hit 1 pharmacophores with enhanced inhibiting activity, e.g., carmofur, bendamustine, triclabendazole, emedastine, and omeprazole, in which omeprazole is the only one binding to the C-terminal domain of SARS-CoV-2 M-pro. Our study demonstrates that the fragment-based approach is a feasible strategy for identifying low-molecular-weight drugs against the SARS-CoV-2 and other potential targets lacking specific drugs.
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